title: 5-Deazaflavin derivatives as inhibitors of p53 ubiquitination by HDM2.
abstract: Based on previous reports of certain 5-deazaflavin derivatives being capable of activating the tumour suppressor p53 in cancer cells through inhibition of the p53-specific ubiquitin E3 ligase HDM2, we have conducted an structure-activity relationship (SAR) analysis through systematic modification of the 5-deazaflavin template. This analysis shows that HDM2-inhibitory activity depends on a combination of factors. The most active compounds (e.g., 15) contain a trifluoromethyl or chloro substituent at the deazaflavin C9 position and this activity depends to a large extent on the presence of at least one additional halogen or methyl substituent of the phenyl group at N10. Our SAR results, in combination with the HDM2 RING domain receptor recognition model we present, form the basis for the design of drug-like and potent activators of p53 for potential cancer therapy.
authors.affiliation: School of Pharmacy & Centre for Biomolecular Sciences, University of Nottingham, University Park, Nottingham NG7 2RD, UK.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Dickens
authors.forename: Patricia
authors.initials: P
authors.lastname: Roxburgh
authors.forename: Andreas
authors.initials: A
authors.lastname: Hock
authors.forename: Mokdad
authors.initials: M
authors.lastname: Mezna
authors.forename: Barrie
authors.initials: B
authors.lastname: Kellam
authors.forename: Karen H
authors.initials: KH
authors.lastname: Vousden
authors.forename: Peter M
authors.initials: PM
authors.lastname: Fischer
mesh_terms: D001665:Binding Sites; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D005415:Flavins / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D062105:Molecular Docking Simulation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D004791:Enzyme Inhibitors; D005415:Flavins; D016159:Tumor Suppressor Protein p53; C019319:5-deazaflavin; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
keywords: Cancer; Deazaflavin; HDM2–p53; Ubiquitin E3 ligase; Ubiquitination inhibitors